Fungal infections after bone marrow transplant

What every physician needs to know:

Invasive fungal infections

What conditions can underlie invasive fungal infections?

Development of an invasive fungal infection occurs when the following three requirements are met: Exposure to a pathogenic fungus, breakdown in antifungal host defenses, and failure (or absence) of effective prophylaxis.

Infections caused by yeasts, especially Candida species, which used to be common in bone marrow transplant (BMT) before the widespread use of antifungal prophylaxis, are an excellent example. Candida species exist as normal commensals in the GI tract and on the skin, and their concentrations at those sites can intensify with the antibacterial treatment that is routinely used in BMT patients. In that context, damage to mucosal and cutaneous barriers caused by cytotoxic chemotherapy and vascular access catheters, coupled with defects in neutrophil function and number, provides a pathway to invasive infection.

Most invasive infections in BMT recipients occur through GI tract invasion during a period of mucositis and neutropenia. This is especially likely in someone who is not receiving azole antifungals, as Candida albicans, the most pathogenic of the Candida species (and also very azole sensitive), can form hyphae to invade through the gut wall. Even with azole prophylaxis, Candida species can break through and cause systemic disease, manifesting most commonly as either a bloodstream infection (candidemia), or as isolated organ disease (hepatosplenic candidiasis).

Dissemination can then occur via invasion into the systemic circulation or portal vasculature. Peripheral manifestations can develop, most frequently involving the eye, heart valves, or skin. Invasion into the portal vasculature can lead directly to hepatic candidiasis, which may not present at the time of infection, but rather, presents after neutrophils return, and evokes chronic inflammation. This is the reason that hepatosplenic disease can result in patients who never have any documented episodes of candidemia.

Infections caused by airborne environmental fungi are another example. Spores (conidia) are frequently inhaled into the airways or the sinuses. In the absence of effective neutrophilic and/or cellular immunity, conidia sporulate into germinated (hyphal) forms, which can both invade the lung (or sinus) tissue and cause inflammation. The risk is significantly increased when there are respiratory tract abnormalities such as epithelial damage due to a viral infection and/or structural damage due to previous lung disease. The filamentous forms are angioinvasive and can spread locally or disseminate through the bloodstream to distant sites (e.g., skin, brain, liver). Aspergillus species are the most common cause of pulmonary fungal infections, and these infections can occur during primary periods of neutropenia and graft-versus-host disease (GVHD). Other pulmonary fungal infections include mucormycosis, scedosporiosis, fusariosis, cryptococcosis, pneumocystosis and in the appropriate geographic locales, endemic mycoses such as histoplasmosis.

Antifungal prophylaxis is key, and has been shown to improve survival in the highest risk patients. Agents that can be given by the oral and IV route (e.g., fluconazole, posaconazole, and voriconazole) are the most important prophylaxis options. For allogeneic BMT recipients with neutropenia, fluconazole provides good protection against candidiasis and is generally well tolerated. Posaconazole and voriconazole are also active against filamentous fungi (principally Aspergillus spp.) and are preferentially used at some centers. Other options are the echinocandins (e.g., micafungin) and amphotericin B (AmB) products, which must be given by the IV route.

Typical length of prophylaxis is for 75 days after transplant and longer if neutropenia persists. In cases of GVHD requiring treatment with immunosuppressive therapy, one of the agents with activity against filamentous fungi (e.g., posaconazole or voriconazole) is used until resolution of significant GVHD. Prophylaxis against Pneumocystis (e.g., TMP/SMX) should be maintained for at least 6 months after transplantation and during other times when patients are receiving immunosuppressants.

What features of the presentation will guide me toward possible causes and next treatment steps?

Invasive candidiasis should be considered as a cause of infection in any BMT recipient who is persistently neutropenic, has GVHD-induced mucositis, and/or has an indwelling intravascular catheter. Most frequently, candidemia presents as a febrile illness, potentially with sepsis-like manifestations. Skin rashes can occur, and appear most frequently as erythematous papules or pustules.

Invasive aspergillosis or other filamentous fungi should be considered as a cause of infection in a BMT recipient who has ongoing fevers of unknown origin despite broad-spectrum antibacterial and anti-Candida therapy, has unexplained lower respiratory tract or sinus symptoms, or new central nervous system (CNS) or cutaneous disease. Patients with prolonged leucopenia, GVHD requiring corticosteroids, and those with anatomic or physiologic respiratory tract and sinus abnormalities are at particularly high risk.

Cryptococcosis and the geographically limited fungal infections (e.g., histoplasmosis, blastomycosis, and coccidioidomycosis) are less common in BMT patients, but should be considered with unexplained presentations of pulmonary, skin, or CNS disease.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

Because cultures are often negative even in the face of disseminated candidiasis, treatment is frequently empiric. Culture of blood, although not sensitive enough to rule-out Candida as a cause of a febrile syndrome, is important to guide therapy, and to measure success of antifungal treatment. Blood cultures should be performed daily after a patient develops candidemia, until a negative result is obtained; in order to minimize the likelihood of organ involvement, therapy should be administered for at least 14 days after the last positive blood culture.

It is important to realize that blood cultures are not very sensitive for Candida species. While newer technologies may enrich for Candida growth, these organisms should be considered as potential causes of febrile illnesses, even in the absence of positive cultures. Several tests that detect circulating beta-D-glucan in blood are being used in medical centers throughout the world.

While these assays are sensitive for detection of fungal components, results are positive in the presence of multiple fungi, including filamentous organisms that cause pulmonary disease. Also, there are multiple causes of false-positive test results, as beta-glucan can be found in many medical products (e.g., gauze, dialysis filters).

Any blood culture that reveals Candida species should be treated as a true candidemia, and not attributed to colonization or contamination; one of the reasons that we treat all positive blood cultures, is that there is an increased risk for subsequent embolic complications, such as endophthalmitis, in people who have “transient” candidemia. By contrast, blood cultures that reveal filamentous organisms are usually contaminants from the laboratory, except with growth of one of the fungi that can sporulate in vivo, such as Fusarium species.

Candida species can present as hepatosplenic candidiasis, especially in people who have had prior episodes of neutropenia concurrent with gastrointestinal (GI) mucositis; risks are especially high in people who have received such therapies in the absence of prophylactic antifungals. This diagnosis should be suspected in people who present with elevated liver enzymes, especially alkaline phosphatase, and fever, potentially with abdominal or flank pain. In this setting, multiple hypodense lesions are usually apparent on ultrasound, computed tomography (CT) scan or magnetic resonance imaging (MRI).

While liver biopsy may be useful to document the cause of disease, and to distinguish between yeasts and other causes of liver abscesses (such as bacteria), negative findings do not rule out hepatosplenic candidiasis, as frequently, the inciting yeast is difficult to find, and the main histopathological finding points to the resultant (frequently granulomatous) inflammatory response.

What imaging studies (if any) will be helpful?

It is not usually necessary to perform additional imaging studies in the presence of a positive blood culture, except in the setting of suspected peripheral manifestations, such as endocarditis (rare, evaluate with echocardiography), or with suspected intra-abdominal or renal abscesses. MRI is more sensitive compared to either ultrasound or CT scan in detecting hepatosplenic candidiasis.

CT scan of the chest and/or sinuses is often useful for pointing clinicians in the direction of an invasive fungal infection. Patients with proven or suspected fungal infections do not need routine CT scans of the head unless there are neurological findings that suggest CNS involvement.

Fungi, especially filamentous organisms such as Aspergillus species, should be considered with presentation of focal pulmonary infiltrates, such as nodules, with or without “halo” or cavitation. In BMT recipients, invasive aspergillosis can present with varied radiographic abnormalities, ranging from isolated to multiple nodules to larger focal infiltrates, sometimes at the same time (Figure 1). These organisms disseminate through the bloodstream, most frequently causing skin lesions and central nervous system lesions.

Figure 1.

Invasive aspergillosis can present with varied radiographic abnormalities, ranging from isolated to multiple nodules to larger focal infiltrates, sometimes at the same time.

If a patient presents with pulmonary abnormalities (nodular opacities or focal infiltrates), that are suggestive of an invasive fungal infection, one should obtain serum galactomannan (GM) and beta-glucan assays, and consider bronchoscopy. GM is an antigen that is expressed by Aspergillus species, and some organisms that are closely related (such as Penicillium species). This has become an important diagnostic test, applied to both blood and bronchoalveolar lavage (BAL) fluid. A positive galactomannan test is highly predictive of invasive aspergillosis when found in the presence of nodular or focal infiltrates. In the past, false-positive tests were noted in people who were receiving drugs that were contaminated with galactomannan, such as piperacillin-tazobactam. This no longer seems to be a cause of false-positive results. An elevated serum beta-glucan level is non-specific, but may be a clue to invasive aspergillosis or Pneumocystis infection in the appropriate clinical context (e.g., lymphocyte dysfunction and/or corticosteroids exposure). In such patients, testing for histoplasmosis (serum or urine antigen) and cryptococcosis (serum antigen) may be needed as well.

BAL is an essential step to diagnosing pulmonary fungal infections, and several studies have demonstrated safety. Use of the galactomannan assay on BAL fluid adds to the sensitivity of diagnosing invasive aspergillosis, and it should be done in addition to culture. Presence of Candida species in respiratory samples, including BAL is typically NOT indicative of infection, but rather of upper tract and airway colonization.

When do you need to get more aggressive tests?

More aggressive tests to document the microbial cause of any systemic illness should be considered when signs and symptoms of the infection are not responding to what should be appropriate antifungal therapy. For instance, biopsy of skin is a good idea when a rash is expanding on antifungal therapy, and biopsy of the liver may be necessary to define the microbial etiology of an expanding liver lesion. However, the caveat is that liver lesions are anticipated to grow even with appropriate antifungal therapy, as this is usually caused by inflammation itself.

When a pulmonary lesion is not responding to an empirical antifungal course, biopsy by video-assisted thoracoscopic surgery (VATS) should be considered. This is important today, when empiric antifungal therapy with voriconazole is frequently used for presumed fungal pneumonia, but may only target Aspergillus species, and not include other filamentous organisms, such as agents of mucormycosis, or bacterial pathogens. It is also important in ruling out non-infectious causes of pulmonary lesions, such as bronchiolitis obliterans.

Sinusitis

Fungi cause both invasive and allergic sinusitis; in the BMT recipient, invasive sinusitis with dissemination into the orbit and/or brain is the most severe manifestation. Typical fungal etiologies include aspergillosis, mucormycosis, and fusariosis. Biopsy of the sinuses is important both to confirm the diagnosis of invasive fungal sinusitis and to identify which organism is the cause, as therapy differs depending on the organism. Invasive fungal sinusitis cannot be ruled out by a “normal” visual examination; biopsy, even blind biopsy performed in the absence of visual necrosis or lesions, is necessary to identify microscopic hyphal mucosal involvement.

Skin lesions

The presence of multiple skin lesions in a patient who has pulmonary findings consistent with fungal pneumonia are suggestive of haematogenous spread, especially with organisms that can undergo in vivo sporulation such as Fusarium species, Alternaria species, and Scedosporium species. Biopsy should be performed to document microbial etiology, as these infections need to be very aggressively treated and prognosis is poor.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Treatment of proven or suspected candidiasis

Candidemia

When Candida infection occurs in a patient who is receiving azole prophylaxis, it is usually caused by one of the azole-resistant species, such as Candida glabrata or Candida krusei. This limits the use of azole antifungals for treatment of invasive candidiasis. In the setting of blood culture revealing an unidentified yeast and/or when such an infection is suspected, initial therapy is typically with an echinocandin (e.g., caspofungin 70 mg x 1 followed by 50 mg/day, micafungin 100 mg/day, or anidulafungin 200 mg x 1 followed by 100 mg/day). These drugs have good activity against the most common causes of invasive infection in people receiving azole prophylaxis, except for some species, such as Candida parapsilosis and increasingly C. glabrata. If the organism is identified as one of these species that may demonstrate relative resistance to echinocandins, therapy may be changed to a lipid AmB formulation at 3-5 mg/kg/day. We usually try to avoid using AmB due to its renal toxicity.

Hepatosplenic candidiasis

Suspect Candida as a cause of hypodense liver lesions, especially in a patient who is relatively azole naive and has had a significant period of neutropenia and mucositis; in these patients, antifungal therapy that targets C. albicans, such as an echinocandin, is the appropriate first step, even without documenting infection with liver biopsy. Lipid formulation of AmB is another option. Treatment should continue for several weeks at which point transitioning to oral fluconazole 400 mg/day can be considered unless there is concern for resistance. Therapy is typically several months or longer and guided by resolution of lesions on imaging.

What other therapies are helpful for reducing complications of candidiasis?

If the source of candidemia is determined to be due to the central venous catheter (CVC) then it should ideally be removed. Intravascular catheters should be removed when possible, even in people with suspected invasion through the GI tract, as the catheter tip can be a nidus for secondary seeding and persistent infection. However, needless removal of an implanted and uninfected catheter can cause harm and the decision to remove the CVC should be individualized. Persistently positive blood cultures are a clue to primary or secondary involvement of a catheter that should be removed.

Although not demonstrated to have a documented impact in randomized trials, people with persistent candidemia and/or sepsis may benefit from granulocyte transfusions, especially if prolonged neutropenia is anticipated.

Treatment of proven or suspected invasive aspergillosis

Therapy for pulmonary fungal infections should be targeted to the organism that is found on culture of lavage fluid (or other respiratory samples). However, in the absence of culture confirmation, we usually start voriconazole (6 mg/kg every 12 hours x 2 doses then 4 mg/kg twice daily) as therapy, except in patients who have had a high amount of exposure in the past, or those who have liver dysfunction or drug interactions that prohibits its use. Visual hallucinations are a common side effect that should be kept in mind. Other options for invasive aspergillosis include isavuconazonium (loading dose 372 mg every 8 hours x 6 doses, followed by maintenance dose of 372 mg twice daily) and a lipid formulation of AmB, which is especially important for patients in whom an azole antifungal cannot be used.

What other therapies are helpful for reducing complications of invasive aspergillosis?

Intravascular catheters should be removed when possible, even in people with suspected invasion through the GI tract, as the catheter tip can be a nidus for secondary seeding and persistent infection. Although not demonstrated to have a documented impact in randomized trials, people with persistent candidemia and/or sepsis may benefit from granulocyte transfusions, especially if prolonged neutropenia is anticipated.

We always consider adding an echinocandin to a voriconazole or an amphotericin formulation in the setting of severe pulmonary invasive aspergillosis. A randomized trial showed that people who received the combination of voriconazole and anidulafungin for aspergillosis had improved survival at 6-weeks compared to voriconazole alone, although the difference failed to meet statistical significance. We believe that there is accumulating evidence that the risk-benefit ratio supports combined agents for primary therapy of documented disease.

Use of granulocyte transfusions in the setting of pulmonary fungal infections is not well supported by data, and considerable risk for pulmonary toxicities decrease our enthusiasm for using them.

Surgical resection of pulmonary fungal lesions should be considered when infiltrates are closely approximating large vessels, and in the setting of severe hemoptysis. Large cavitary lesions do not necessarily have to be resected, and can regress in size with appropriate therapy.

Treatment of proven or suspected mucormycosis

When there is recovery of an agent of mucormycosis from biopsy or lavage and/or with suspicion for such an infection (e.g., palatine or sinus infection with associated necrosis) we recommend treatment with lipid formulation of amphotericin B at 5-7.5 mg/kg/day and surgical resection of the area of necrosis. An occasional exception to this is pulmonary mucormycosis, where medical management alone may suffice unless necrosis is extensive or progressive despite antifungal therapy.

There are some in vitro and in vivo data suggesting that combination therapy with an echinocandin may help; we usually consider adding an echinocandin in the setting of severe disease (despite lack of randomized, controlled trials). Posaconazole is an azole that has good activity against these organisms, and it can be used after an initial “induction” regimen with the amphotericin formulation. Isavuconazonium (loading dose 372 mg every 8 hours x 6 doses, followed by maintenance dose of 372 mg twice daily) has been recently approved for treatment of mucormycosis, but experience with this drug is limited at this time.

What should you tell the patient and the family about prognosis?

Attributable mortality of candidiasis is difficult to estimate, given the complex medical conditions that exist at the time of candidemia. Most people clear Candida bloodstream infections without peripheral complications or death, however, studies have shown that approximately 20-30% of people who develop this infection die within 30 days (most likely due to multiple underlying causes, and sometimes, sepsis).

Death after diagnosis of aspergillosis is relatively common, occurring in approximately 30-50% of people within 12 weeks of diagnosis in the most recent studies, although the actual attributable mortality is difficult to estimate (likely approximating 20%).

“What if” scenarios.

Ocular involvement (choroidal and vitreal dissemination) is one of the more frequent peripheral manifestations of Candida species bloodstream invasion. Eye exams should be performed on people with positive blood cultures. In those with neutropenia, dilated funduscopic examinations should be performed soon after neutrophil recovery as ophthalmological findings may be minimal until that time. If there are signs of endophthalmitis or vitritis, vitrectomy may be necessary. As azole antifungals penetrate the eye best, we usually add an azole (fluconazole, unless the bloodstream organism is C. krusei, in which case, voriconazole has good activity).

It is important to dose voriconazole aggressively, as people who are receiving the oral formulation at 200 mg twice daily frequently do not have high enough levels. This seems to be especially problematic in younger patients. Therapeutic drug monitoring by high-performance liquid chromatography (HPLC) with a target trough level of 2.0-5.5 mcg/mL is a good idea, if results are available in reasonable time.

What other clinical manifestations may help me to diagnose fungal infections after bone marrow transplant?

Colonization with Candida species predicts invasive disease, especially through the GI tract. The same is true for anyone noted to be colonized with Aspergillus species, especially in the respiratory tract. The exception is Aspergillus niger, which is a frequent inhabitant of the GI tract, and not usually associated with higher risks for infection.

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